Abstract
The involvement of histamine H3 receptors (H3Rs) in memory is well known, and the potential of H3R antagonists in therapeutic management of neuropsychiatric diseases, e.g., Alzheimer disease (AD) is well established. Therefore, the effects of histamine H3 receptor (H3R) antagonist E159 (2.5–10 mg/kg, i.p.) in adult male rats on dizocilpine (DIZ)-induced memory deficits were studied in passive avoidance paradigm (PAP) and in novel object recognition (NOR) using pitolisant (PIT) and donepezil (DOZ) as standard drugs. Upon acute systemic pretreatment of E159 at three different doses, namely 2.5, 5, and 10 mg/kg, i.p., 2.5 and 5 but not 10 mg/kg of E159 counteracted the DIZ (0.1 mg)-induced memory deficits, and this E159 (2.5 mg)-elicited memory-improving effects in DIZ-induced amnesic model were moderately abrogated after acute systemic administration of scopolamine (SCO), H2R antagonist zolantidine (ZOL), but not with H1R antagonist pyrilamine to the animals. Moreover, the observed memory-enhancing effects of E159 (2.5 mg/kg, i.p.) were strongly abrogated when animals were administered with a combination of SCO and ZOL. Furthermore, the E159 (2.5 mg)-provided significant memory-improving effect of in DIZ-induced short-term memory (STM) impairment in NOR was comparable to the DOZ-provided memory-enhancing effect, and was abolished when animals were injected with the CNS-penetrant histamine H3R agonist R-(α)-methylhistamine (RAMH). However, E159 at a dose of 2.5 mg/kg failed to exhibit procognitive effect on DIZ-induced long-term memory (LTM) in NOR. Furthermore, the results observed revealed that E159 (2.5 mg/kg) did not alter anxiety levels and locomotor activity of animals naive to elevated-plus maze (EPM), demonstrating that improved performances with E159 (2.5 mg/kg) in PAP or NOR are unrelated to changes in emotional responding or in spontaneous locomotor activity. These results provide evidence for the potential of drugs targeting H3Rs for the treatment of neuropsychiatric disorders, e.g., AD.
Highlights
The memory-enhancing effect observed for E159 was dose-dependent, since the improvement of memory provided by E159 (2.5 mg/kg) in the DIZ-induced amnesia model was significantly higher when compared to the higher doses (5 and 10 mg/kg), demonstrating that an optimum in memoryenhancing effect was observed when the H3 receptors (H3Rs) antagonist/inverse agonist E159 was applied at the lowest dose (2.5 mg/kg), and an off-target effect for E159 at higher doses (5 and 10 mg/kg) might have been observed in the current study (Figure 2)
The results observed in the current study showed that acute systemic post-training administration of E159 (2.5 mg/kg) significantly improved the time spent to explore the novel object compared with the familiar object, and delivered a type of short-term memory (STM) (Figure 5)
The observed results show that the non-imidazole H3R antagonist E159 reduces DIZ-induced cognitive deficits in passive avoidance paradigm (PAP) and novel object recognition (NOR) task in adult male rats
Summary
The main representative character of AD as a neurogenerative disease and related dementias, e.g., cognitive deficit associated with schizophrenia (CDS), is the progressive decline in cognitive performance (Medhurst et al, 2007, 2009; Silva et al, 2014), and enhancing cognitive functions in these conditions embodies a multifaceted task, given the fact that various brain neurotransmission systems and several brain regions are involved in the progress of these conditions (Khan et al, 2015; Shimizu et al, 2015; Sadek et al, 2016a,c). Several H3R antagonists/inverse agonists have been previously found to counteract DIZ-induced memory deficits in rodents (Witkin and Nelson, 2004; Passani and Blandina, 2011; Sadek and Stark, 2015; Sadek et al, 2016c) previous preclinical as well as clinical experiments revealed that antagonists at N-methyl-D-aspartate receptors (NMDARs), e.g., ketamine, promote cognitive deficits in healthy humans and exaggerate symptomatic parameters in patients with schizophrenia (Luby et al, 1959; Ghoneim et al, 1985; Javitt and Zukin, 1991; Krystal et al, 1994; Malhotra et al, 1997; Brown et al, 2013).
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